27-hydroxycholesterol is an endogenous selective estrogen receptor modulator
27-hydroxycholesterol is an endogenous selective estrogen receptor modulator
复制标题
DOI：
10.1210/me.2007-0383
复制
发表时间：
2008-01-01
影响因子：
--
通讯作者：
McDonnell, Donald P.
中科院分区：
文献类型：
--
作者：
DuSell, Carolyn D.;Umetani, Michihisa;McDonnell, Donald P.
选择性雌激素受体（ER）调节剂（SERMs）是雌激素受体配体，其相对激动剂/拮抗剂活性以细胞和启动子依赖的方式变化。这种选择性的分子基础可以归因于这些配体诱导内质网结构明显改变的能力，从而导致协同激活剂和协同抑制剂的不同募集。SERM活性是否局限于合成配体，或者体内是否存在以类似方式起作用的分子仍未解决。然而，最近的观察表明，氧甾醇结合内质网并拮抗17 β -雌二醇（E2）在血管壁上的作用，这类配体可能具有SERM活性。我们在此证明27-羟基胆固醇（27HC）是循环中最普遍的氧甾醇，具有SERM的功能，其功效在不同终点评估时有所不同。重要的是，在乳腺癌细胞模型中，27HC正调控基因转录和细胞增殖。利用组合肽噬菌体展示，我们已经确定27HC诱导ER α和ER β的独特构象变化，将其与E2和其他serm区分开来。因此，与其他内质网配体一样，27HC的独特药理活性似乎与其影响内质网结构和调节辅因子募集的能力有关。综上所述，这些数据表明27HC是一种在乳腺癌细胞中具有部分激动剂活性的内源性SERM，并提示它可能影响乳腺癌的病理。此外，考虑到27HC和胆固醇之间的产物-前体关系，我们的研究结果对肥胖/高胆固醇个体的乳腺癌风险有影响。
Selective estrogen receptor (ER) modulators (SERMs) are ER ligands whose relative agonist/ antagonist activities vary in a cell- and promoter-dependent manner. The molecular basis underlying this selectivity can be attributed to the ability of these ligands to induce distinct alterations in ER structure leading to differential recruitment of coactivators and corepressors. Whether SERM activity is restricted to synthetic ligands or whether molecules exist in vivo that function in an analogous manner remains unresolved. However, the recent observation that oxysterols bind ER and antagonize the actions of 17 beta-estradiol (E2) on the vascular wall suggests that this class of ligands may possess SERM activity. We demonstrate here that 27-hydroxycholesterol (27HC), the most prevalent oxysterol in circulation, functions as a SERM, the efficacy of which varies when assessed on different endpoints. Importantly, 27HC positively regulates both gene transcription and cell proliferation in cellular models of breast cancer. Using combinatorial peptide phage display, we have determined that 27HC induces a unique conformational change in both ER alpha and ER beta, distinguishing it from E2 and other SERMs. Thus, as with other ER ligands, it appears that the unique pharmacological activity of 27HC relates to its ability to impact ER structure and modulate cofactor recruitment. Cumulatively, these data indicate that 27HC is an endogenous SERM with partial agonist activity in breast cancer cells and suggest that it may influence the pathology of breast cancer. Moreover, given the product-precursor relationship between 27HC and cholesterol, our findings have implications with respect to breast cancer risk in obese/hypercholesteremic individuals.